The Choroid Plexus Is Permissive for a Preactivated Antigen-Experienced Memory B-Cell Subset in Multiple Sclerosis

Area of Science:

• Neuroimmunology
• Cellular Biology
• Multiple Sclerosis Pathogenesis

Background:

• B cells play a crucial role in multiple sclerosis (MS) pathogenesis, with memory B cells accumulating in the cerebrospinal fluid (CSF).
• While B cell trafficking across the blood-brain barrier is studied, transmigration through the blood-CSF barrier (BCSFB) remains poorly understood.

Purpose of the Study:

• To investigate the mechanisms of B cell interaction with the choroid plexus and transmigration into the CSF.
• To analyze the role of specific chemokines and B cell activation states in BCSFB diapedesis.
• To characterize the phenotype and migratory behavior of intrathecal B cells in MS patients.

Main Methods:

• Isolation of circulating B cells from healthy controls (HC) and MS patients.
• Utilized an inverted cell culture filter system of human choroid plexus papilloma (HIBCPP) cells to assess transmigration rates.
• Employed immunofluorescence, electron microscopy, and qRT-PCR to analyze migration routes, gene expression, and chemokine involvement; screened intrathecal B cell transcriptomes.

Main Results:

• Spontaneous B cell transmigration was low but significantly increased with chemokines CXCL-12/CXCL-13, further boosted by pre-activation, occurring via paracellular and transcellular routes.
• Migrating B cells showed upregulated genes for activation/migration, enhanced CXCR4/CXCR5 expression, and were predominantly isotype class-switched memory cells.
• This migratory subset exhibited enhanced chemotaxis in MS patients and was found in intrathecal cells of active MS patients; natalizumab treatment modulated this trafficking.

Conclusions:

• The BCSFB is a critical gate for activated, potentially harmful B cells to enter the CSF in MS.
• Chemokines CXCL-12 and CXCL-13 are key mediators of B cell diapedesis across the BCSFB.
• Class-switched memory B cells represent a key pathogenic subset trafficking into the CSF in active MS.